The Case Against Antidepressants for Bipolar Depression: Findings from STEP-BD

Do you prescribe antidepressants for your patients with bipolar depression? If so, think again, and consider results from the Systematic Treatment Enhancement Program – Bipolar Disorder (STEP-BD) studies. This was the largest federally funded study of bipolar disorder treatment and it included important randomized clinical trials involving subsamples of the 4360 patients enrolled. Among the significant findings were the following:
1. Antidepressants (bupropion, paroxetine) are not more effective than placebo for bipolar depression (24% for the antidepressants vs 27% for the placebo in a 6-month trial).1 The antidepressants, when added to a mood stabilizer, did not induce more switches into mania (10% vs 11%) but the patients who participated in the study were probably at very low risk for switching. However, patients with bipolar depression with mixed features (defined as having 2 or more manic symptoms with their depression, like agitation and racing thoughts) developed manias over the next several months that were more severe compared with placebo-treated patients.
2. A group of 86 bipolar patients that had been put on an antidepressant when depressed and seemed to respond, was identified. Some were rapid cyclers (4 or more episodes per year). All were also on mood stabilizers such as lithium, valproate, or a second-generation antipsychotic. These patients were randomized to stay on their antidepressants or discontinue them. The rapid cycling patients who were continued on their antidepressant had triple the number of depressions per year compared with the non-rapid cyclers. In the patients whose antidepressant was discontinued, there was no difference in the rate of depressions between rapid and non-rapid cycling individuals. Thus, depressive morbidity and cycling were worsened by continuation of an antidepressant in rapid cyclers.2
3. In another STEP-BD study, prospective data were collected on the first 1500 patients looking for evidence of the antidepressant-associated chronic irritable dysphoria (ACID) syndrome described in previous case reports.3 It had been proposed that ACID was caused by treating patients who had bipolar depression with an antidepressant. The patient sample included 63% bipolar I patients with depression, with most of the rest being bipolar II. The researchers identified 83 patients in whom a depressive episode developed during the study period and for whom there was at least 1 year of follow-up information. Those who received an antidepressant for their depression had a 10-fold higher risk for ACID than the patients who were antidepressant free. ACID did not seem to occur in the natural course of bipolar disorder. It only occurred in those who received antidepressants.

Conclusion
Findings from STEP-BD studies indicate that antidepressants should be avoided in most cases in treating acute depression in patients with bipolar disorder. Rather, one should choose from among five medications with a reasonable evidence-base for effectiveness and safety in treating or at least preventing bipolar depressions, namely: lithium, quetiapine, lamotrigine, lurasidone, and cariprazine—or combinations of these.